Gemcitabine enhances OSI-027 cytotoxicity by upregulation of miR-663a in pancreatic ductal adenocarcinoma cells

Am J Transl Res. 2019 Jan 15;11(1):473-485. eCollection 2019.


Pancreatic ductal adenocarcinoma (PDAC) is well-known to be the most deadly malignancy with the worst survival rate of all cancers. Gemcitabine-based chemotherapy is the most common treatment option for pancreatic ductal adenocarcinoma. However, it offers little therapeutic value in many cases due to the rapid development of chemoresistance. MicroRNAs (miRNAs) have been found to play pivotal roles in the chemotherapeutic resistance of PDAC. In the present study, we examined the molecular basis for the effective combination of OSI-027 and gemcitabine (GEM). Firstly, we identified a specific miRNA expression profile in PDAC cells after treatment with either of these drugs. We found that miR-663a was significantly upregulated after treatment with GEM and downregulated after OSI-027 treatment. With combination of the two drugs, miR-663a level was lower than the GEM group, but higher than the OSI-027 group. Real-time quantitative PCR confirmed these observations. To further establish the role of miR-663a in OSI-027 and GEM resistance in pancreatic cancer, we transfected PDAC cells with miR-663a mimic or miR-663a inhibitor. Cell viability and proliferation assays showed that miR-663a mimic enhanced drug sensitivity, while inhibitor promoted drug resistance. Moreover, we found that the combined effect of OSI-027 and GEM disappeared after inhibiting miR-663a. Our study clearly demonstrates that GEM upregulates miR-663a, thereby promoting the sensitivity of pancreatic cancer cells to OSI-027. Our study suggests that miR-663a expression may be a useful indicator of the potential for chemoresistance and provides a potential new therapeutic target to avert chemoresistance in PDAC.

Keywords: OSI-027; Pancreatic ductal adenocarcinoma (PDAC); chemoresistance; gemcitabine; microRNA.